Author:
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Cai, Ning Sheng; Quiroz, César; Bonaventura, Jordi; Bonifazi, Alessandro; Cole, Thomas O.; Purks, Julia; Billing, Amy S.; Massey, Ebonie; Wagner, Michael; Wish, Eric D.; Guitart, Xavier; Rea, William; Lam, Sherry; Moreno Guillén, Estefanía; Casadó-Anguera, Verónica; Greenblatt, Aaron D.; Jacobson, Arthur E.; Rice, Kenner C.; Casadó, Vicent; Newman, Amy H.; Winkelman, John W.; Michaelides, Michael; Weintraub, Eric; Volkow, Nora D.; Belcher, Annabelle M.; Ferré, Sergi
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Abstract:
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Identifying non-addictive opioid medications is a high priority in medical sciences, but μ-opioid receptors mediate both the analgesic and addictive effects of opioids. We found a significant pharmacodynamic difference between morphine and methadone that is determined entirely by heteromerization of μ-opioid receptors with galanin Gal1 receptors, rendering a profound decrease in the potency of methadone. This was explained by methadone's weaker proficiency to activate the dopaminergic system as compared to morphine and predicted a dissociation of therapeutic versus euphoric effects of methadone, which was corroborated by a significantly lower incidence of self-report of 'high' in methadone-maintained patients. These results suggest that μ-opioid-Gal1 receptor heteromers mediate the dopaminergic effects of opioids that may lead to a lower addictive liability of opioids with selective low potency for the μ-opioid-Gal1 receptor heteromer, exemplified by methadone. |